Lower alkyl



United States Patent O-[DI(LOWER ALKYL)-4-LOWER ALKOXY-BEN- ZOYL] -LOWER ALKYL RESERPATES Jacob Szmuszkovicz, Portage Township, Kalamazoo County, and Richard V. Heinzelman, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application April 5, 1957 Serial No. 650,846

11 Claims. (Cl. 260-287) The present invention is concerned with physiologically active chemical compounds related to reserpine and is more particularly concerned with methyl reserpate O- (dialkyl-4-alkoxybenzoates) represented by the following formula:

0 CH alkyl Of particular interest are compounds of the foregoing formula wherein the alkyl radicals are the same or different lower-alkyl radicals, the term lower-alkyl being defined in this specification and appended claims as an alkyl radical containing from one to six carbon atoms, inclusive. The methyl reserpate O-(dialkyl-4-alkoxybenzoates) of this invention are prepared by esterification of methyl reserpate with an esterifying agent to introduce a dialkyl-4-alkoxybenzoate radical, as more fully illustrated by the examples. Methyl reserpate O-(dialkyl-4- alkenoxybenzoates) of copending application Serial No. 650,847, filed April 5, 1957, now abandoned, also can be catalytically hydrogenated to methyl reserpate O- dialkyl-4-alkoxybenzoates), as illustrated by Example 5.

This application is a continuation-in-part of our copending application Serial No. 593,299, filed June 22, 1956, now abandoned.

It is an object of the present invention to provide methyl reserpate O-(dialkyl-4-alkoxybenzoates), particularly the methyl reserpate O-[di-(loWer-alkyl)-4-(loweralkoxy)-benzoates], which are physiologically active agents of high potency having hypotensive and sedative properties and which have a superior ratio of hypotensive to sedative activity and a superior therapeutic ratio when compared with reserpine. The compounds of the present invention can be substituted for reserpine in known reserpine-containing pharmaceutical compositions such as tablets, injectables, and elixirs. Other objects and uses of the present invention will be apparent to one skilled in the art.

In this invention, representative O-esters of methyl reserpate include the 2,6-dimethyl-4-propoxybenzoate, 2,6 dimethyl 4 methoxybenzoate, 2,6 dimethyl 4- isopropoxybenzoate, 2,6-dimethyl-4-hexyloxybenzoate, 2,6-dimethyl-4-butoxybenzoate, 2,6-diethyl-4-propoxybenzoate, 2,6-dibuty1-4-methoxybenzoate, 2-methyl-6-ethyl- 4-propoxybenzoate, and other 2,6-dialkyl-4-alkoxybenzoates, the 3,5-dimethyl-4-propoxybenzoate, 3,5-dimethyl- 4-isobutoxybenzoate, 3,5-diethyl 4methoxybenzoate, 3,5- dipropyl-4-propoxybenzoate, 3,5-dihexyl-4-propoxyben= "ice zoate 3,S-dipropyl-4-ethoxybenzoate, and other 3,5- dialkyl-4-alkoxybenzoates, the 2,3-dimethyl-4-methoxybenzoate, 2,3-dimethyl-4-propoxybenzoate, 2,3-dimethyl- 4-pentyloxybenzoate, 2-methyl-3-ethyl-4-propoxybenzoate, 2,3-diisobutyl-4-isobutoxybenzoate, and other 2,3- dialkyl-4-alkoxybenzoates, the 2-isopropyl-5-methyl-4- ethoxybenzoate, 2 methyl-S-isopropyl-4-ethoxybenzoate, 2,5-dipropyl-4-propoxybenzoate, 2,5-dimethyl-4-methoxybenzoate, 2,S-diethyl-4-propoxybenzoate, 2-methyl-5- isopropyl-4-nrethoxybenzoate, and other 2,5-dialkyl-4- alkoxybenzoates, particularly those dialkyl-4-alkoxybenzoates wherein the alkyl and alkoxy radicals each contain less than seven carbon atoms. The dimethyl-4- alkoxybenzoates wherein the alkoxy radical contains from one to three carbon atoms, inclusive, in general are more particularly preferred, the 2,6-dimethyl-4-alkoxybenzoates of this class in general being still more preferred. The most preferred compound is the 2,6-dimethyl-4-(n-propoxy)-benzoate esterp It is to be understood that within the scope of this invention are included the methyl reserpate 0-(dialkyl-4-alkoxybenzoate) free base and acid addition salts thereof such as the sulfates, hydrochloride, phosphates, hydrobromide, hydroiodide, acetate, propionate, benzoate, citrates, maleates, succinates, salicylate, phenylacetate, uand fi-phenylpropionates, fl-cyclopentylpropionate, etc.

In preparing the methyl reserpate O-esters of this invention the preferred esterifying agent is the acid chloride of the dialkyl-4-alkoxybenzoic acid. However, if desired, the acid bromide, or the acid anhydride, or other dialkyl- 4-alkoxybenzoic acid compound suitable for esterification of methyl reserpate can be employed, all these dialkyl-4-alkoxybenzoic acid compounds being prepared from the dialkyl-4-alkoxybenzoic acid by conventional procedures, for example, reaction of a dialky1-4-alkoxybenzoic acid With thionyl chloride provides the corresponding dialkyl-4-alkoxybenzoyl chloride. The dialkyl-4-alkoxybenzoic acids, in turn, are prepared by prior art procedures or procedures analogous thereto, for example, dialkyl-4-hydroxybenzoic acids (US. Patent 2,243,694) are converted, via their esters, to dialkyl-4- alkoxybenzoic acids by conventional etherification and hydrolysis procedures well-known in the art. The 2,3- dialkyland 2,6-dialkyl-4-hydroxybenzoic acids are obtained, for example, by aromatization, such as by heating in the presence of a palladium catalyst, of corresponding 2,3-dialkyland 2,6-dialkyl-4-oxo-2-cyclohexene-l-carboxylic acid esters (US. Patent 2,582,252 and copending application SN. 432,033, filed May 24, 1954), followed by hydrolysis of the resulting 2,3-dialkyland 2,6-dialky1- 4-hydroxybenzoic acid esters. The 2,5-dialkyl-4-alkoxybenzoic acids are obtained, for example, by nitration of 1,4-dialkylbenzenes to produce 2nitro-1,4-dialkylbenzenes, the nitro group then being reduced to an amino group which is diazotized and hydrolyzed to a hydroxy group, and the thus-obtained 2,5-dialkylphenol etherified to produce 2,5-dialkyl-l-alkoxybenzenes which are chloromethylated in the 4-position and the chloromethyl group then converted to a carboxyl group, for example, by alkaline hydrolysis of the chloromethyl group to a hydroxymethyl group followed by oxidation of the hydroxymethyl group to a carboxyl group with potassium permanganate. The 3,5-dialkyl-4-alkoxybenzoic acids are obtained, for example, from 4-chlorophenol by acylation in the 2-position, for example. with an acyl chloride and aluminum chloride according to the Friedel-Crafts acylation method, reduction of the 2-acyl radical to an alkyl radical, for example, with zinc and hydrochloric acid according to the Clemmensen reduction method, acylation, as described above, of the thus-produced 2-alkyl-4- chlorophenol in the 6-position followed by reduction of the acyl radical, as described above, to produce 2,6-

dialkyl-4-chlorophenol, elimination of the 4-chloro atom, for example, by treatment with sodium and alcohol, and etherification of the phenolic hydroxyl group, as described above, to obtain 2,6-dialkyl-l-alkoxybenzene, and introduction of a 4-carboxyl radical, for example, by 4- bromination followed by Grignard reagent formation with magnesium and subsequent treatment with carbon dioxide, to obtain the desired 3,5-dialkyl-4-alkoxybenzoic acid. 3,5-dialkyl-4-alkoxybenzoic acids also are obtained by diazotization and acid hydrolysis of the corresponding 3,5-dialkyl-4-aminobenzoic acid followed by etherification, as described above, of the thus-obtained 3,5-dialky1- 4-hydroxybenzoic acid as its ester, and hydrolysis of the ester. The Fries rearrangement of para-unsubstituted dialkylphenol acetates provides dialkyl-4-hydroxyacetophenones which on oxidation of the acetyl group, for example, with potassium permanganate, provide dialkyl-4- hydroxybenzoic acids which are etherified, as described above, to provide the desired dialkyl-4-alkoxybenzoic acids. Hydrogenation of the dialkyl-4-alkenoxybenzoic acid of copending application Serial No. 650,847, filed April 5, 1957, with hydrogen in the presence of a palladium catalyst also provides desired dialkyl-4-alkoxybenzoic acids.

The following examples are illustrative only and are not to be construed as limiting the scope of the present invention.

Example 1.-Methyl reserpate -(dialkyl-4-alk0xybenz0ates)preferred general procedure A cold solution of 4.14 grams (0.01 mole) of methyl reserpate in fifty milliliters of pyridine is prepared and 0.03 mole of the dialkyl-4-alkoxybenzoyl chloride is added thereto during a five-minute period with stirring. The resulting reaction mixture is maintained at room temperature (between about fifteen and about 35 degrees centigrade) for approximately twenty hours. Then the reaction mixture is cooled in an ice bath and a mixture of 100 milliliters of water and fifty grams of ice is added with stirring. The aqueous-organic mixture is extracted with four 50-milliliter portions of chloroform. The combined chloroform extracts are washed with four 50-milliliter portions of five percent aqueous potassium hydroxide solution, and the combined aqueous alkaline wash solutions are extracted once with fifty milliliters of chloroform. The combined chloroform solutions then are washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent the solution is evaporated to dryness under reduced pressure. The residual crude methyl reserpate O-(dialkyl-4-alkoxybenzoate) is purified by crystallization and/or chromatographic procedures in a conventional manner.

Example 2.Methyl reserpate 0-(2,6-dimethyl-4-propoxybenzoate) A solution of 0.5 gram of methyl reserpate in eight milliliters of pyridine is prepared and 0.55 gram of 2,6-dimethyl-4-(n-propoxy)-benzoyl chloride is added thereto, dropwise with stirring, the reaction mixture being cooled in an ice bath. The resulting mixture is maintained at room temperature for 24 hours, after which a mixture of ice and Water is added. The aqueous mixture is extracted with methylene dichloride and the methylene dichloride extract is washed with three percent aqueous sodium hydroxide solution followed by saturated aqueous sodium chloride solution. The washed extract is dried over anhydrous sodium sulfate and the dried extract is evaporated to dryness. The residue is chromatographed over neutral alumina using methylene dichloride for elution to obtain purified methyl reserpate O-(2,6-dimethyl-4-propoxybenzoate). Highly purified product, 82 milligrams, is obtained by subsequent recrystallization from ether, melting point 200 to 204 degrees centigrade.

4 Analysis.Calcd. for C H N O C, 69.51; H, 7.33; N, 4.63. Found: C, 68.95; H, 6.55; N, 4.49.

Example 3.--Methyl reserpate O-(2,6-dimethyl-4-methoxybenzoate) Methyl reserpate is esterified with 2,6-dimethyl-4- methoxybenzoyl chloride according to the general procedure of Example 1. The crude dark brown solid (eight grams) obtained is dissolved in thirty milliliters of benzene and chromatographed over 300 grams of neutral alumina. The methyl reserpate O-(2,6-dimethyl-4- methoxybenzoate) is eluted with benzene containing fifteen percent chloroform. The compound is obtained as a yellow powder which does not readily crystallize.

Example 4.--Methyl reserpate 0-(2-methyl-6-ethyl-4- propoxybenzoate) Methyl reserpate is esterified with 2-methyl-6-ethyl-4- (n-propoxy)-benzoyl chloride according to the general procedure of Example 1. The crude product (10.4 grams) is dissolved in thirty milliliters of benzene and chromatographed over 300 grams of neutral alumina. The methyl reserpate O-(2-methyl-6-ethyl-4-propoxybenzoate) is eluted with benzene containing ten percent chloroform. The compound crystallizes on trituration with methanol and is purified by recrystallization from methanol; melting point under vacuum 145 to 147 degrees centigrade with sintering at 119 degrees centigrade.

Analysis.-Calcd. for C H N O C, 69.88; H, 7.49; N, 4.53. Found: C, 69.41; H, 7.39; N, 4.81.

Example 5 .-M ethyl reserpate 0-(3,5-dipr0pyl-4-pr0p0xybenzoate) Methyl reserpate O-(3,5-dipropyl-4-allyloxybenzoate) (0.7 gram) dissolved in 100 milliliters of percent ethanol is hydrogenated in the presence of 0.25 gram of ten percent palladium-on-carbon catalyst, at room temperature and at 35 pounds per square inch pressure. After the absorption of hydrogen ceases, the catalyst is removed by filtration and the filtrate is evaporated to dryness under reduced pressure, at room temperature. The residue crystallizes upon trituration with ether. There is thusobtained 0.32 gram of methyl reserpate O-(3,5-dipropyl- 4-propoxybenzoate), melting point 193 to 196 degrees centigrade. Upon further evaporation of the ether, there is obtained a second crop, weight 0.12 gram.

Example 6.-Methyl reserpate O-(Z-methyl-S-ethyllpropoxy-benzoate) Methyl reserpate is esterified with 2-methyl-3-ethyl-4- (n-propoxy)-benzoyl chloride according to the general procedure of Example 1 to produce methyl reserpate O-(2- methyl-3-ethyl-4-propoxybenzoate) Example 7.--Methyl reserpate O-(Z-methyl-S-isopropyl- 4-ethoxybenz0ate) According to the general procedure of Example 1, methyl reserpate is esterified with 2-methyl-5-isopropyl- 4-ethoxybenzoyl chloride to produce methyl reserpate O- (2-methyl-5-isopropyl-4-ethoxybenzoate) In the same manner as shown in Examples 1 through 7 other methyl reserpate O-(dialkyl-4-alkoxybenzoates) are prepared from methyl reserpate and the appropriate acid chloride esterifying agent, or by catalytic hydrogenation of a methyl reserpate O-(dialkyl-4-alkenoxybenzoate), including the following O-esters of methyl reserpate: 2,6 dimethyl 4 isopropoxybenzoate, 2,6 dimethyl 4 hexyloxybenzoate, 2,6 dimethyl 4 butoxybenzoate, 2,6 diethyl 4 propoxybenzoate, 2,6 dibutyl 4 methoxybenzoate, 3,5 dimethyl 4 propoxybenzoate, 3,5 dimethyl 4 isobutoxybenzoate, 3,5 diethyl 4 methoxybenzoate, 3,5 dihexyl 4 propoxybenzoate, 3,5 dipropyl 4 ethoxybenzoate, 2,3 dimethyl 4 methoxybenzoate, 2,3 dimethyl 4 propoxybenzoate, 2,3 dimethyl 4 pentyloxybenzoate, 2 methyl 3 ethyl 4 propoxybenzoate, 2,3 diisobutyl 4 isobutoxylbenzoate, 2 isopropyl 5 methyl 4 ethoxybenzoate, 2,5 dipropyl 4 propoxybenzoate, 2,5 dimethyl 4 methoxybenzoate, 2,5 diethyl 4 propoxybenzoate, 2 methyl 5 isopropyl 4 methoxybenzoate, and other 2,3-, 2,5-, 2,6-, and 3,5-dialkyl-4-alkoxybenzoates. By substituting other alkyl reserpates, for example, ethyl reserpate, propyl reserpate, butyl reserpate, isobutyl reserpate, hexyl reserpate, etc. there are obtained the corresponding esters of such other alkyl reserpate which have like utility.

Following the procedures of Examples 1 through 7, but substituting methyl deserpidate, methyl raunescate or methyl raujemidate for the methyl reserpate, there are prepared the corresponding O-(dialkyl-4-alkoxybenzoate) esters of methyl deserpidate, methyl raunescate, and methyl raujemidate, respectively, wherein the ester radicals are those named previously in the description and examples, which esters are useful for the same purpose and employed in the same manner as the corresponding 0-(dialkyl-4-alkoxybenzoate) esters of methyl reserpate. The following examples are illustrative:

Example (i-Methyl deserpidate 0-(2,6-dimethyl-4-pr0- poxybenzoate) Following the procedure of Example 1 substituting methyl deserpidate for the methyl reserpate and using 2,6-dimethyl-4-propoxybenzoyl chloride as the dialkyl-4- alkoxybenzoyl chloride, there is obtained methyl deserpidate O-(2,6-dimethyl-4-propoxybenzoate) Example 9.Methyl raunescate O-(2,6-dimethyl-4-propoxybenzoate) Following the procedure of Example 1 substituting methyl raunescate for the methyl reserpate and using 2,6- dimethyl-4-propoxybenzoyl chloride as the dialkyl-4-alkoxybenzoyl chloride, there is obtained methyl raunescate O-(2,6-dimethyl-4-propoxybenzoate).

Example 10.-Methyl raujemidate 0-(2, 6-methyl-4-propoxybenzoate) Following the procedure of Example 1 substituting methyl raujemidate for the methyl reserpate and using 2,6- dimethyl-4-propoxybenzoyl chloride as the dialkyl-4-alkoxybenzoyl chloride, there is obtained methyl raujemidate O-(2,6-dimethyl-4-propoxybenzoate) In the same manner as shown in Examples 1 through 7 other dialkyl-4-alkoxybenzoic acid esters of methyl deserpidate, methyl raunescate, and methyl raujemidate are prepared by reacting the latter with the appropriate acid chloride esterifying agent, or by catalytic hydrogenation of the corresponding O-(clialkyl-4-alkenoxybenzoate), including the following O-esters of methyl deserpidate, methyl raunescate, and methyl raujemidate: 2,6-dimethyl- 4-isopropoxybenzoate, 2,6-dimethyl-4-hexyloxybenzoate,

2,6 dimethyl 4 butoxy benzoate, 2,6 diethyl 4 propoxybenzoate, 2,6-dibutyl-4-methoxybenzoate, 3,5-dimethyl-4-propoxybenzoate, 3,5-dirnethyl-4-isobutoxybenzoate, 3,5-diethyl-4-methoxybenzoate, 3,5-dihexyl-4-propoxybenzoate, 3,5 dipropyl 4 ethoxybenzoate, 2,3 dimethyl- 4 methoxybenzoate, 2,3 dimethyl 4 propoxybenzoate, 2,3 dimethyl 4 pentyloxybenzoate, 2 methyl 3 ethyl 4 propoxybenzoate, 2,3 diisobutyl 4 isobutoxybenzoate, 2 isopropyl 5 methyl 4 ethoxybenzoate, 2,5 dipropyl 4 propoxybenzoate, 2,5 dimethyl 4- methoxybenzoate, 2,5-diethyl-4-propoxybenzoate, 2-methyl-5-isopropyl-4-methoxybenzoate, and other 2,3-, 2,5- 2,6-, and 3,5-dialkyl-4-alkoxybenzoates. By substituting other alkyl deserpidates, raunescates, and raujemidates, for example, ethyl, propyl, butyl, isobutyl, hexyl deserpidate, raunescate, and raujemidate, there are obtained the corresponding esters of such other alkyl deserpidate, raunescate, and raujemidate which have like utility.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. Lower-alkyl reserpate O-[di-(lower-alkyl)-4-(loweralkoxy) -benzoate] 2. Methyl reserpate O-[di-(loWer-alkyl)-4-(lower-alkoxy)-benzoatel.

3. Methyl reserpate O-[2,3-di-(lower-alkyl)-4-(loweralkoxy) -benz0ate] 4. Methyl reserpate O-[2,5-di-(lower-alkyl)-4-(loweralkoxy -benzoate] 5. Methyl reserpate O-[2,6-di-(lower-alkyl)-4-(loweralkoxy( -benzoate] 6. Methyl reserpate O-[3,5-di-(lower-alkyl)-4-(loweralkoxy) -benzoatel.

7. Methyl reserpate O-(2-methyl-3-ethyl-4-propoxybenzoate).

8. Methyl reserpate O-(2-methyl-5-isopropyl-4-ethoxybenzoate).

9. Methyl reserpate O-(2,6-dimethyl-4-propoxybenzoate).

10. Methyl reserpate 0-(2,6-dimethy1-4-methoxybenzoate).

11. Methyl reserpate O-(3,5-dipropyl-4-propoxybenzoate).

References Cited in the file of this patent UNITED STATES PATENTS 2,789,112 Taylor Apr. 16, 1957 2,789,113 Taylor Apr. 16, 1957 

1. LOWER-ALKYL RESERPATE O-(DI-(LOWER-ALKYL)-4-(LOWERALKOXY)-BENZOATE). 